Myeloid DCs are central in the

orchestration of innate and acquired immune responses and in the maintenance of self-tolerance [1]. DC development involves three functionally and phenotypically distinct stages for which the terms “precursors,” “immature,” and “mature” are commonly used [2-5]. DCs precursors originate in the bone marrow, circulate via the bloodstream to reach target tissues, and take up residence at sites of potential pathogen entry, where they differentiate into immature DCs (iDCs) specialized for antigen capture [2, 4, 6]. Peripheral blood monocytes recruited from the circulation to inflammatory sites can also serve as iDC precursors [7, 8]. iDC redistribution in the tissues is determined by the local microenvironment through the production of chemotactic mediators, activation selleck products of inflammatory chemokine receptors, and regulation of adhesion molecules [7, 8]. Tissue

injury, inflammation, and transformation cause dramatic changes of the microenvironment, modulating iDC phenotype and function and promoting maturation into (m)DCs [7-14]. A common denominator of injured and inflamed tissues is the presence of low partial oxygen pressure (pO2), which creates a unique microenvironment affecting cell phenotype, gene expression profile, and functional behavior Kinase Inhibitor Library [10, 11, 15, 16]. Response to hypoxia is primarily under the molecular control of a family of hypoxia-inducible transcription factors, composed of the constitutive HIF-1β subunit and an O2-sensitive α subunit (HIF-1α/-2α), which binds and transactivates the hypoxia responsive element (HRE) present in the promoter of many hypoxia-inducible genes [11, 15-17]. DC development

from monocytic precursors recruited at pathological sites occurs under the setting of reduced pO2. Recent studies have reported that HIF-1α accumulates in hypoxic Sodium butyrate DCs and that O2 levels similar to those present in diseased tissues can impact on DC differentiation, maturation, and activation [10, 11, 18-24]. Hypoxia promotes the onset of a migratory phenotype in iDCs through the upregulation of inflammatory chemokine receptors and motility-related genes with consequent increased responsiveness to specific chemoattractants [18-20] and a proinflammatory state in mDCs by increasing the expression of genes coding for proinflammatory and Th1-priming chemokines/cytokines [24]. DCs integrate stimulatory and inhibitory signals present in the microenvironment through a defined repertoire of cell surface receptors, and deregulated expression of these molecules may result in aberrant responses characterized by amplification of inflammation and loss of tolerance [5, 7-9, 25-27].